PROJECT SUMMARY Pulmonary fibrosis is a leading cause of death worldwide. With a median survival of only 2.5 years after diagnosis, it is responsible for millions of deaths worldwide and billions in health care costs each year. Besides mortality, pulmonary fibrosis, of which the idiopathic type is most common, brings about tragic morbidity. Without a known cause of idiopathic pulmonary fibrosis, very few preventive strategies are practical and until recently no therapeutic options were available. The two drugs that were approved for this indication provide some attenuation of the disease, but despite this, clinical decline almost invariably occurs. The long-term goal of STXPC is to bring a drug to the clinic that can reverse the progression of pulmonary fibrosis with more complete results than the current standards of care with reduced or equally acceptable adverse effects. Phenotypic screens identified an FDA approved drug that blocks fibroblast activation in vitro and represses bleomycin-induced pulmonary fibrosis in vivo. In continuation of these efforts, three near term objectives are proposed to set the foundation for future IND-enabling studies. These objectives are: 1) to establish the mechanism of action for the drug, 2) to validate efficacy in additional animal models while also testing alternate routes of administration, and 3) to initiate feasibility studies for the development of an inhalable formulation of the drug. To address the mechanism of action, the hypothesis that the drug activates casein kinase 1 to promote the degradation of critical drivers of the myofibroblast phenotype including YAP/TAZ and/or ?-catenin will be tested. This will be accomplished using genetic and pharmacological techniques in cell culture assays. Two forms of the drug will be tested against in vivo models of pulmonary fibrosis, including bleomycin and asbestos-induced models, through multiple administration routes to establish minimum effective doses and to evaluate oral availability. The final aspect of this proposal includes a collaboration with a contract manufacturing organization to test feasibility of developing a stable nebulizable solution or suspension of the drug that could be used in future animal testing, and possibly lead to a clinical product. Development of this formulation would provide a direct topical medication for the lung, circumventing any inadequacies regarding GI absorption or liver metabolism and minimizing systemic side effects. Pulmonary fibrosis is a severe condition that warrants significant efforts to bring new therapeutics forward for clinical testing. The research team has identified a repurposable drug that holds early potential to reverse the effects of pulmonary fibrosis acting through a unique mechanism, but requires reformulation for an adequate means of administration.